A guinea pig model of Zika virus disease Abstract: Zika virus (ZIKV) has recently emerged as a new public health threat. ZIKV infection has been linked to the development of severe fetal abnormalities that include spontaneous abortion, stillbirth, hydranencephaly, and microcephaly. No effective therapies currently exist for treating patients infected with ZIKV. Very little information is available on the natural history of ZIKV infection in pregnant women and its outcomes. Development of animal models that reflect true clinical disease is a significant barrier to advancing our understanding of ZIKV disease and its long-term pathophysiological effects. Recently, we demonstrated that guinea pigs are susceptible to infection by a contemporary American strain of ZIKV. We also demonstrated that after subcutaneous inoculation, ZIKV is neurotropic in guinea pigs. The principal objective of the proposed exploratory research is to characterize and utilize the guinea pig model to study in utero ZIKV infection, sexual transmission and ZIKV neurological disease. With this model in place, we will examine the relationship between clinical disease and the derangements observed in the immune system, the nervous system and viral load. In aim 1, we will develop ZIKV in utero infection model in guinea pigs. In Aim 2, we will develop ZIKV sexual transmission model in guinea pigs. In Aim 3, we will develop ZIKV neurological disease model in guinea pigs. The proposed research is highly innovative as it will be the first study to employ the guinea pig model to characterize in utero transmission and pathogenesis of ZIKV. The findings from this study will have a significant impact on understanding mechanisms associated with ZIKV transmission to the fetus, pregnancy outcomes, pathogenesis of sexual transmission, short-term neurological sequelae in infants, and other ZIKV manifestations in infants including developmental delays and physical disorders. This study will help understand pathogenic mechanisms underlying the development of ZIKV associated neurological disease. Also, this model system will form the basis to understand the basic biology of ZIKV infection and disease, and to develop strategies to prevent transmission of ZIKV to the fetus, and for evaluating vaccines and therapeutics.